Novolog Mix Drug Information

• Inspect visually before use. Appearance should be uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles ( 2.1 ).
• NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature ( 2.1 ).
• Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm (2.1).
• Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation ( 2.1 ).
• Rotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1) .
• Do not administer intravenously or use in insulin infusion pumps ( 2.1 ).
• NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack) (2.2) .
• Individualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal ( 2.2 ).
• Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness ( 2.2 ).
• When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed ( 2.2 ). 2.1 Important Preparation and Administration Instructions
• Always check insulin labels before administration [see Warnings and Precautions (5.4)] .
• Inspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.
• NOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.
• When using the: o Vial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately. o NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.
• The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
• Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
• Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
• Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.
• Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions ( 6.1 , 6.3 )].
• Do not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
• Do not mix NOVOLOG MIX 70/30 with any other insulins. 2.2 Dosage Recommendations
• NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).
• Individualize the dosage of NOVOLOG MIX 70/30 based on the patient's metabolic needs, blood glucose monitoring results and glycemic control goal.
• Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )] .
• When switching from another insulin to NOVOLOG MIX 70/30, a different dosage of NOVOLOG MIX 70/30 may be needed [see Warnings and Precautions (5.2)] .
• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )]. 2.3 Dosage Modifications for Drug Interactions Dosage modification may be needed when NOVOLOG MIX 70/30 is used concomitantly with certain drugs [see Drug Interactions (7)] .

• The following adverse reactions are also discussed elsewhere:
• Hypoglycemia [ see Warnings and Precautions (5.3) ]
• Hypoglycemia Due to Medication Errors [ see Warnings and Precautions (5.4) ]
• Hypersensitivity reactions [ see Warnings and Precautions (5.5) ]
• Hypokalemia [ see Warnings and Precautions (5.6) ] Adverse reactions observed with insulin therapy include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash and pruritus (6) . To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Clinical trials are conducted under widely varying designs, therefore, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The data in:
• Table 1 reflects the exposure of 55 patients with type 1 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 43 years old. Sixty-four percent were male and 100% were White. The mean body mass index (BMI) was 26.1 kg/m 2 . The mean duration of diabetes was 15 years.
• Table 2 reflects the exposure of 85 patients with type 2 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 63 years old. Fifty-four percent were male and 100% were White. The mean body mass index (BMI) was 28.1 kg/m 2 . The mean duration of diabetes was 15 years. Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse reactions that occurred for NOVOLOG MIX 70/30-treated patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. The trial was a three-month, open-label trial in patients with type 1 or type 2 diabetes who were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30. Table 1: Adverse Reactions that Occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients Treated with NOVOLOG MIX 70/30 NOVOLOG MIX 70/30 (n=55) Preferred Term N % Hypoglycemia 38 69 Headache 19 35 Influenza-like symptoms 7 13 Dyspepsia 5 9 Back pain 4 7 Diarrhea 4 7 Pharyngitis 4 7 Rhinitis 3 5 Skeletal pain 3 5 Upper respiratory tract infection 3 5 Table 2: Adverse Reactions that Occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients Treated with NOVOLOG MIX 70/30 NOVOLOG MIX 70/30 (n=85) Preferred Term N % Hypoglycemia 40 47 Upper respiratory tract infection 10 12 Headache 8 9 Diarrhea 7 8 Neuropathy 7 8 Pharyngitis 5 6 Abdominal pain 4 5 Rhinitis 4 5 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG MIX 70/30 . The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for NOVOLOG MIX 70/30 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with NOVOLOG MIX 70/30. The incidence of severe hypoglycemia in adult patients receiving subcutaneous NOVOLOG MIX 70/30 was 16% and 4% for type 1 and type 2 diabetes patients respectively at 12 weeks [see Clinical Studies (14)] . Allergic Reactions Patients have experienced reactions such as erythema, edema or pruritus at the site of NOVOLOG MIX 70/30 injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, have required discontinuation of NOVOLOG MIX 70/30. Severe cases of generalized allergy (anaphylaxis) have been reported. Adverse Reactions Associated with Insulin Initiation and Glucose Control Intensification Intensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy Long-term use of insulin, including NOVOLOG MIX 70/30, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.1)] . Weight Gain Weight gain can occur with insulins, including NOVOLOG MIX 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. Peripheral Edema Insulins, including NOVOLOG MIX 70/30, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NOVOLOG MIX 70/30 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In a 3-month study with an extension in adult patients with type 2 diabetes, 100% of patients who received NOVOLOG MIX 70/30 were positive for anti-insulin antibodies (AIA) at least once during the first 12 months of the study including 91.4% that were positive at baseline. A total of 91.4% of patients who received NOVOLOG MIX 70/30 were positive for anti-drug antibodies (ADA) at least once during the first 12 months of the study, including 62.1% that were positive at baseline. In a type 2 diabetes clinical trial of NOVOLOG MIX 70/30, initial increase in titers of antibodies to insulin followed by a decrease approaching to baseline values was observed in NOVOLOG MIX 70/30 and Novolin 70/30 treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of NOVOLOG MIX 70/30. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors in which other insulins have been accidentally substituted for NOVOLOG MIX 70/30 have been reported. Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

• The table below presents clinically significant drug interactions with NOVOLOG MIX 70/30. Table 3: Clinically Significant Drug Interactions with NOVOLOG MIX 70/30 Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.
• Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7) .
• Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones (7) .
• Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7) .
• Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7) .

Pregnancy Risk Summary There are no available data with NOVOLOG MIX 70/30 in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy . In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of 1 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia.

These effects were similar to those observed in rats administered regular human insulin . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a HbA 1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials.

Animal Data Fertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats.

In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day.

These doses are approximately 8 times the human subcutaneous dose of 1 unit/kg/day for rats and equal to the human subcutaneous dose of 1 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

Pediatric Use Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients with diabetes mellitus.

• 70/30 is contraindicated:
• During episodes of hypoglycemia [ see Warnings and Precautions (5.3) ]
• In patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients [see Warnings and Precautions (5.5)]
• Do not use during episodes of hypoglycemia (4) .
• Do not use in patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients (4) .

Excess insulin administration may cause hypoglycemia and hypokalemia . Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.

Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.